Hemophilia Landscape Updates - December 2023

by Dr. David Clark

Several of the updates below are from the annual meeting of the American Society of Hematology (ASH) on December 9–12, 2023 in San Diego. Copies of the abstracts (summaries) can be obtained for free on the meeting website, https://www.hematology.org/meetings/annual-meeting.

X-CHROMOSOME INACTIVATION AND BLEEDING IN CARRIERS OF HEMOPHILIA B

12/11/23 Women have two X-chromosomes, unlike men who have an X and a Y. The factor IX gene is on the lower right arm of the X-chromosome, the one that is missing on the Y-chromosome. Therefore, women have two copies of the factor IX gene in each cell, while men only have a single copy.

 In order to prevent hazardous interactions between the two X-chromosomes in women, one copy of the X-chromosome in each cell is inactivated. X-chromosome inactivation (XCI) is thought to be a random process in each cell, so a woman who has one X-chromosome with a mutated factor IX gene and one X-chromosome with a good factor IX gene should end up with about 50% of her cells containing the X with the mutation and 50% with the good X without the mutation. (This is like flipping a coin. If you do it enough times, you should come out with about a 50-50 ratio of heads and tails.)

 Therefore, the average carrier should have about 50% of normal factor IX activity: half of her liver cells are producing “good” factor IX and half of her liver cells are producing mutated factor IX. However, we know that the XCI process can be skewed – that instead of a 50-50 split, it can vary to as much as an 80-20 or worse split. If the 80% of her liver cells are producing “good” factor IX, a woman’s factor IX level would be expected to be about 80% of normal and she should not have hemophilia.

On the other hand, with an 80-20 split, if the 80% are the cells producing the mutated factor IX, she would only have a factor level of about 20% and she would have hemophilia. In either case, she would still be a carrier, because she could still pass on the mutated gene to her children.

 Currently the best theory about why some carriers have hemophilia is that they have a skewed XCI, although we don’t know why that happens. That may be about to change. At ASH, a group from Penn State Hershey Medical Center presented data suggesting that skewed XCI might not be the reason after all, or at least not the whole reason. They found in 15 subjects that there was no correlation between the degree of XCI skewing and factor levels. This finding adds to a growing list of studies of XCI and hemophilia, some of which show no correlation with XCI skewing and some of which do show a correlation. This simply tells us that we don’t know enough.

The ASH authors recognize this and propose that the answer might be much more complex, especially for hemophilia B. For one thing, now that we know that the factor IX bound inside the blood vessel walls is important for clotting. Since a carrier has both “good” factor IX and mutated factor IX in her bloodstream, one might be out-competing the other for the binding spots in the vessel wall, and that could affect her bleeding tendencies.

Now that we’re recognizing that women do get hemophilia, there is bound to be more research to find out why. That research could also help males with hemophilia, since there is still a lot we don’t know there. [Cygan PH et al., ASH abstract 3990]

WOMEN GET INHIBITORS, TOO!

1/14/20 While researching the above piece on women with hemophilia, I came across an article in my files that could be important for some. On 1/14/20, Shellye Horowitz wrote an article in Hemophilia News Today that pointed out that women with hemophilia can get inhibitors, too. An inhibitor is an antibody that blocks the action of infused clotting factor. Men are now recommended to get inhibitor testing at least once a year, and women should be tested, too.

The CDC now recommends that anyone with hemophilia or with von Willebrand Disease type 3 be tested annually for inhibitors. One of the early signs of an inhibitor is bleeding that doesn’t stop, even after a substantial amount of clotting factor has been used. [Horowitz S, Hemophilia News Today article 1/14/20] 

THE CARRIERS ULTRASOUND PROJECT

12/9/23 Not much is known about joint damage in women with hemophilia. The Carriers Ultrasound Project (CUT) wants to change that. CUT recruited 28 carriers of hemophilia (24 As; 4 Bs) and 30 controls, women who had no family or personal history of hemophilia.

The carriers showed a higher prevalence of bleeding and more joint-related symptoms, including pain, than the controls. Curiously, the carriers showed their symptoms on the Hemophilia Joint Health Score (HJHS) questionnaire but showed no difference from the controls on the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) survey. HEAD-US is designed to detect early changes in joint health in men with hemophilia but may fall short for women. 

A high body mass index (BMI) was also correlated with increased joint bleeding among the carriers. Joint damage is apparently common among carriers, even those without hemophilia. More research is needed. [Kronenfeld RS et al., ASH abstract 29] 

FACTOR LEVELS AND BLEEDING RISK IN HEMOPHILIA PATIENTS PLAYING SPORTS

5/24/23 A group of researchers in The Netherlands looked at bleeding risk as a function of factor level for hemophilia patients playing sports. In 125 subjects aged 6–49 (90% As, 10% Bs, 48% severe), they found that sports injuries were rare. Only 26 sports-related injuries were recorded in 15,999 sports exposures (0.16%). Most of the subject’s injuries and bleeding episodes were not sustained during sports activities.

There was no correlation between sports-associated bleeding and hemophilia severity, joint health, sports risk category or sport intensity. The only correlation was with factor levels at the time of injury. They found that people with factor levels below 10% had more than twice the bleeding risk as people with factor levels above 10%. This shows the importance of keeping your factor levels high when playing sports. [Versloot O et al., Haemophilia, online ahead of print 5/24/23] 

NO DIFFERENCE IN QUALITY OF LIFE BETWEEN PEOPLE WITH SEVERE HEMOPHILIA A AND B

2/15/23 We periodically see articles looking at differences in severity between people with hemophilia A and B. Some see this as a “competition,” but the real value is in trying to find differences between the two hemophilias that might provide clues to better understanding of both diseases.

A large group in Scandinavia looked at health-related quality of life (HRQoL) using several questionnaires in 63 people with severe hemophilia B compared with 63 people with severe A. The As in the control group were matched by age, gender and treatment modality (on- demand or prophylaxis) to the Bs. No inhibitor patients were included.

Mobility problems were reported by 46% of Bs and 44% of As. Pain or discomfort was reported by 62% of Bs and 56% of As. Strikingly, anxiety or depression was reported by 33% of Bs and only 17% of As. Looking at the questionnaire responses overall, there was no significant difference in HRQoL between the As and Bs. The largest negative impact was from poor joint health in both groups.

The real takeaway from the study is that both As and Bs had impaired HRQOL, even though most subjects were on prophylaxis. There is still a need for improved treatments for hemophilia. [Kihlberg K et al., Haemophilia, online ahead of print 2/15/23] 

IS MILD REALLY MILD? IS MODERATE REALLY MODERATE?

People with mild or moderate hemophilia B (including women) often don’t receive the treatment they need, even in the U.S. Much research focusses on severe hemophilia, so we know relatively little about mild and moderate hemophilia. Several papers over the past year are trying to change that.

10/12/22 One study looked at the use of clotting factor in people with non-severe hemophilia by doing an analysis of past studies. They found some information for hemophilia A but only sparse information for non- severe patients with hemophilia B and for women with hemophilia. In general, they give a rationale that prophylaxis be started early in life in people with significant bleeding, regardless of their factor level. [Iorio A et al., Haemophilia, online ahead of print 10/12/22]

1/25/23 A group of researchers from Argentina looked at the “mildness” of mild hemophilia. They focused specifically on arthropathy (joint damage) in 85 subjects (19 Bs) and 510 joints (ankles, elbows and knees). The cohort’s average age was 35.9 years, and they found that 90.5% of patients over 20 years old had arthropathy. Only 28% of patients had no joint damage and 72% had at least one joint with arthropathy. They found a significant difference in body mass index (BMI) in which the group with arthropathy had an average BMI of 28, while those without arthropathy had an average BMI 0f 20.3.

The median age at diagnosis was 3 years (range 1 to 7) for the no-arthropathy group and 10 (4 to 19) for the subjects with arthropathy. That shows the importance of early diagnosis, especially if the child is from a family with a history of hemophilia. Another significant predictor of joint damage is a history of muscle hematomas. A history of muscle hematoma was present in 65.2% of those with arthropathy but only 20.8% of those without. [Daffunchio C et al., Haemophilia, online ahead of print 1/25/23]

5/10/23 At the WFH Comprehensive Care Summit in May in Buenos Aires, the same group of Argentinian researchers presented data on the physical and social impact of mild hemophilia. They report that the key determinant of quality of life for those with mild hemophilia is joint health. Studying the same 85 subjects/510 joints, they found that 61 patients had at least one joint with damage (defined as a HEAD-US score ≥1). The most affected joint was the ankle.

A total of 56 subjects had at least one hospitalization due to hemophilia with the most common reasons being an illiac psoas hematoma, musculoskeletal surgery and hemarthrosis (joint bleeding), in that order. Probably because they tend to go for so long without treatment, joint damage and quality of life were both associated with age. [Landro M et al., WFH Comprehensive Care Summit, abstract PP-TH-019. Abstracts in Haemophilia, 29(S2) 2023]

10/7/23 A group of researchers from The Netherlands looked at bleeding patterns in patients with moderate hemophilia who bleed like severes, i.e., those who have a severe bleeding phenotype even though their factor levels are ≥1% of normal. (Your phenotype is how you actually bleed. Your genotype predicts your factor level, which predicts how you are expected to bleed. They don’t always agree.)

In 116 subjects, they found that 21% had a severe bleeding phenotype and 46% of those were on prophylaxis. Moderate patients with a severe bleeding phenotype treated on-demand had a higher median ABR of 7, compared to those on prophy who had a median ABR of 2. The on-demand patients also had lower qualities of life. [Verhagen MJA et al., J Thromb Haemost, online ahead of print 10/7/23]

12/11/23 Finally, at ASH a group of researchers from Spain updated a previous study on joint damage in non- severe hemophilia patients. They looked at the effects of age, baseline factor level and global hemostatic capacity (GHC) in 98 non-severe patients, including one moderate hemophilia B patient and four mild B patients. Even with so few Bs, the findings are probably applicable to most mild and moderate hemophilia patients, A or B.

About 56% of the moderate patients and 45% of the mild patients had joint damage. Target joints were observed in about 9% of the mild patients. There was no correlation between factor level or GHC and joint damage. Joint damage did increase with age, reinforcing earlier findings. Their conclusion is that more attention should be paid to joint damage in milds and moderates so it can be determined whether new protocols are needed for diagnosis, prevention and treatment. [Rico AM et al., ASH abstract 3986]

These studies have a common pattern. Many patients with mild and moderate hemophilia (including women) need as much medical attention and clotting factor treatment as patients with severe hemophilia. They definitely experience joint bleeds, but those often go unnoticed because of their low frequency. However, noticed or not, those bleeds contribute to joint damage and can lead to arthropathy and lower quality of life down the road. 

IMPROVED JOINT HEALTH WITH EXTENDED HALF-LIFE (EHL) PRODUCTS

5/10/23 Continuing on the subject of joint health, two papers at the WFH Comprehensive Care Summit looked at improved joint health after use of EHL products. In the past, when patients were on standard half-life (SHL) products and many patients were still using on-demand treatment, we never knew whether joints would heal if one could take enough factor IX. Back then, we were happy just to get severe patients’ factor levels above 1% of normal.

Imagine the cost (not to mention the number of infusions) it would have taken to get them even above 5% and into the mild range. EHL products were originally developed to reduce the number of infusions, but serendipitously they also give patients higher trough levels and fewer joint bleeds.

Sanofi presented a theoretical analysis of historical data for their EHL product Alprolix. Using Pettersson scores to rate joint damage (zero is the best and 13 is the worst), they projected that a person starting prophylaxis with Alprolix at age 12 with no joint issues (a score of zero) would only have a score of 5.0 by age 70. In contrast, a patient using on-demand treatment from age 12 on would have a total score of 32.0 by age 70. (The scores add up, so a score of 32 could be four joints with scores of 8.0 each, or any other combination.) This shows the value of prophylactic treatment compared with on-demand care.

An interesting aspect of their model is that it shows that if an on-demand patient switches to prophy, even as late as age 51, their score at age 70 would be reduced to 18.4, a big difference. Switching earlier could lead to even lower joint damage scores by age 70. [Olive M et al., WFH Comprehensive Care Summit, abstract PP-WE-024. Abstracts in Haemophilia, 29(S2) 2023]

A group from Greece looked at 63 patients (17 Bs: 12 on-demand, 5 late prophylaxis) switching to prophylaxis with EHL products. They monitored the patients for ABR and joint health before switching and every six months thereafter for up to four years. They found that the median ABR was reduced from 4.0 (range 2 – 10) in the group that had been on prophy to 2.0 (0 – 5) after switching to EHL products. The on-demand group who had a median ABR of 20 (18 – 35) before switching also ended up with an ABR of 2.0 afterward.

In this study, they used the Hemophilia Joint Health Score (HJHS) to rate joint damage and found an improvement over time. The median HJHS was reduced from 31.25 (17 – 58) to 21.3 (14 – 54) by year four. This shows that joints can actually improve with adequate treatment. [Christidi SD et al., WFH Comprehensive Care Summit, abstract PP-WE-040. Abstracts in Haemophilia, 29(S2) 2023]

IMPORTANCE OF YKL-40 PROTEIN IN JOINT DAMAGE

12/11/23 We don’t really know the cause of joint damage in hemophilia. We know that it is caused by blood in the capsule surrounding the joint, and it seems that iron from that blood is involved. But drilling down deeper, we don’t really know the causes of the chemical changes taking place in the joint. Now a group from Greece has shown that a protein called YKL-40 is probably involved. YKL-40 is a known protein that is associated with joint diseases like rheumatoid arthritis and osteoarthritis. It is produced in arthritic joints by immune cells and chondrocytes (cells that produce cartilage).

They found that levels of YKL-40 in the bloodstream were significantly higher in hemophilia patients than in the control group without hemophilia. They also found that patients with arthropathy (joint damage) tended to have higher circulating levels of YKL-40 than either hemophilia patients without joint damage or hemophilia patients with active bleeds. Thus YKL-40 might be a cause of joint degradation, and even if it isn’t, it appears to be a marker of joint degradation activity. Measuring YKL-40 in the blood might be a good alternate indicator of ongoing joint damage, even at otherwise undetectable levels, rather than imaging. [Michalopoulou A et al., ASH abstract 3996] 

SHOULD ADULT SEVERE PATIENTS BE ON PROPHYLAXIS?

5/10/23 At the WFH Comprehensive Care Summit, another group of Argentinian researchers presented an evaluation of real-world bleeding and factor use in adults with severe hemophilia. A total of 89 patients (74 As; 15 Bs; all male) over 21 years of age with severe hemophilia A or B were included in the study. The average age was 35.8 years (range 22 – 67) and all patients were on standard half-life (SHL) products.

 The 46 on-demand patients have an average age of 38 and an average ABR of 24.5 bleeds/year. The prophy group has an average age of 43 and an average ABR of 2.5 bleeds/year. Those results suggest pretty convincingly that older severe patients would probably do better on prophylaxis. The only advantage that the on-demand group had is that they used about half the amount of factor. That might help pay their joint surgery bills.

 We always point out that every patient is different. If you are older, severe and using on-demand treatment with few bleeds, you may be fine as you are. However, if you are having more than a couple bleeds per year, you might want to talk to your physician about switching to prophylaxis. It could significantly improve your joint health and your overall quality of life.

If you are concerned about the number of infusions, you could potentially try an extended half-life product. [Martinez M et al., WFH Comprehensive Care Summit, abstract PP-WE-007. Abstracts in Haemophilia, 29(S2) 2023]

HETEROTOPIC OSSIFICATION IN HEMOPHILIA

12/9/23 Heterotopic ossification (HO) is growth of bone where it’s not supposed to be growing, often in muscle tissue. This is a newly found complication of hemophilia, which has been discovered because of the increasing use of ultrasound in hemophilia care. It is emerging as an unforeseen complication of contusions (bruises) and injury-related muscle bleeding in hemophilia. A group of U.S. and international researchers looked at 29 cases from nine HTCs who represented hemophilia A and B in all severities.

The most common areas for HO were the thigh and hip, but also included the upper arm and hand. All cases were due to blunt trauma except for four in the psoas (large muscles in the hip) and one elbow. It happened mostly from deep muscle bleeds where the muscle is close to bone (24/29 cases: 83%).

Only three patients were on prophylaxis at the time of injury (one severe A, one severe B and one moderate B). HO was discovered on average at 23 days post- injury (range 11 to 60) with most cases discovered by a physical therapist (22/29 cases) or physician (2/29 cases). The increased detection of HO is primarily due to the increasing use of ultrasound imaging.

This study confirms that HO is a complication of deep bleeds, especially in patients not on prophylaxis. More study is needed. [Steiner BUK et al., ASH abstract 1248]